Bordetella Spp. Utilize T3SS To Promote Secretion of IL1RA Leading to Long-Term Per-sistent Infections
A common feature of pathogens is their ability to suppress host immune responses. Understanding the molecular mechanisms and the common pathways that bacteria utilize to block host immune signaling cascade might provide novel avenues for vaccine and therapeutic development. Preventable infectious diseases remain one of the major causes of morbidity and mortality worldwide and the current rise in antibiotic resistance is increasing this burden. Bordetella spp. are respiratory pathogens that cause the long-term illness known as whooping cough. Bordetella infections cause over 150,000 deaths each year, despite a vaccine being available. In our studies, we used the mouse pathogen B. bronchiseptica to investigate the pneumonic stage of disease, which very well mimics the fatal disease caused by B. pertussis. In our previous work we discovered a B. bronchiseptica mutant, RB50{Delta}btrS, that clears rapidly from the lungs of mice and generates protective immunity that lasts for at least 15 months post-challenge. Combining the mouse immunological tools and both bacteria, the wildtype RB50 and mutant RB50{Delta}btrS, which persists for up to 56 days and clears in 14-21 days, respectively, we investigated the mechanisms by which the wildtype B. bronchiseptica blocks host immune response to cause long term lung infection. Previous research indicated eosinophils as critical for rapid clearance of the mutant bacteria from the lungs. In vitro assays with eosinophils demonstrated that the RB50{Delta}btrS mutant strain promotes the secretion of pro-inflammatory signals. In contrast, infection of eosinophils with RB50 promoted the secretion of anti-inflammatory signals such as IL1RA. Interestingly, IL1RA was also increased in the lungs of mice infected with the wildtype but not with the mutant RB50 strain. Infection with RB50{Delta}bscN, which lacks a functional type 3 secretion system (T3SS), was sufficient to prevent IL1RA induction suggesting that the bacterial effector responsible for IL1RA upregulation is a substrate of the T3SS. Supplementation with IL1RA after infection with RB50 or RB50{Delta}btrS resulted in increased lung bacterial burden for both bacterial strains. However, more rapid clearance of RB50 was observed after infection of mice in which IL1RA was knocked out. Furthermore, anti-IL1RA antibody treatment promoted rapid clearance of not only RB50 but also the human pathogens B. pertussis and B. parapertussis. This suggests that IL1RA may be a promising therapeutic target to treat severe cases of whooping cough. Overall, this work demonstrates that Bordetella spp. induces IL1RA expression to promote persistence using the T3SS. Since other bacteria have also been shown to target IL1RA, this may be a conserved bacterial mechanism to promote host-immune suppression.